Ivabradine-Stimulated Microvesicle Release Induces Cardiac Protection against Acute Myocardial Infarction

Abstract

Ivabradine can reduce heart rate through inhibition of the current I(f) by still unexplored mechanisms. In a porcine model of ischemia reperfusion (IR), we found that treatment with 0.3 mg/kg Ivabradine increased plasma release of microvesicles (MVs) over Placebo, as detected by flow cytometry of plasma isolated from pigs 7 days after IR, in which a tenfold increase of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) containing (both high and low-glycosylated) MVs, was detected in response to Ivabradine. The source of MVs was investigated, finding a 37% decrease of CD31+ endothelial cell derived MVs, while CD41+ platelet MVs remained unchanged. By contrast, Ivabradine induced the release of HCN4+ (mostly cardiac) MVs. While no differences respect to EMMPRIN as a cargo component were found in endothelial and platelet derived MVs, Ivabradine induced a significant release of EMMPRIN+/HCN4+ MVs by day 7 after IR. To test the role of EMMPRIN+ cardiac MVs (EMCMV), H9c2 cell monolayers were incubated for 24 h with 107 EMCMVs, reducing apoptosis, and increasing 2 times cell proliferation and 1.5 times cell migration. The in vivo contribution of Ivabradine-induced plasma MVs was also tested, in which 108 MVs isolated from the plasma of pigs treated with Ivabradine or Placebo 7 days after IR, were injected in pigs under IR, finding a significant cardiac protection by increasing left ventricle ejection fraction and a significant reduction of the necrotic area. In conclusion ivabradine induces cardiac protection by increasing at least the release of EMMPRIN containing cardiac microvesicles.

Effectiveness and safety of ivabradine in the treatment of acute myocardial infarction: a systematic review and meta-analysis

“…The mechanisms of ivabradine reducing the resting heart rate and improving cardiac function in patients with AMI are as follows: (I) ivabradine can bind to the sinus node I f channel to inhibit the I f current, reduce the sinus node autonomy, and slow down the heart rate (26,27); (II) slowing down the heart rate can prolong the diastolic period, increase myocardial oxygen supply and coronary perfusion, increase cardiac output, and improve cardiac function; (III) heart rate is positively correlated with ventricular volume and heart rate reduction can reduce ventricular volume load, reduce myocardial work and oxygen consumption, and improve exercise tolerance (28,29). Formed by the degradation of BNP precursor secreted by ventricular myocytes, NT-proBNP is negatively correlated with LVEF and reflects the changes of cardiac function in patients with AMI (30), which can be reduced by ivabradine via improved cardiac function.…”

Preclinical models of congestive heart failure, advantages, and limitations for application in clinical practice

“…In addition, pharmacological support to avoid arrhythmogenic behavior, and sometimes ventricular fibrillation (V-FIB) cardioversion procedures are mandatory in many cases. However, the procedure also offers to perform cardiac preconditioning, the event that occurs when patients undergo coronary occlusion and reperfusion in short and repeated times, prior to a longer temporary occlusion, a mechanism previously described of myocardial cardioprotection ( Heusch and Rassaf, 2016 ), and reduced arrhythmogenic behavior ( Ramirez-Carracedo et al, 2020 ). In addition, if percutaneous occlusion of the coronary artery last no longer than 60 min part of ischemic tissue remains contractile (myocardial salvage), allowing to perform studies of cardiac protection ( Santos-Gallego et al, 2016 ).…”

The role of ivabradine in doxorubicin-induced cardiotoxicity: exploring of underlying argument

“…Combined with trimetazidine, IVN reduces the risk of acute cardiac injury in patients undergoing percutaneous coronary intervention as a result of an anti-ischemic effect mediated by a decrease in myocardial oxygen consumption (Chen 2021 ). It has been shown that IVN induces the release of protective microvesicles from endothelial cells, which promote cell proliferation and reduce cardiac necrosis following ischemic reperfusion injury (Ramirez-Carracedo et al 2020 ). IVN promotes expression of extracellular matrix metalloproteinase is induced, which prevents the development of myocardial necrosis (Ramirez-Carracedo et al 2020 ).…”